Age is a major risk factor for a wide range of human diseases, such as cancer, diabetes, neurodegeneration and heart disease. Specifically, aging is associated with high incidence of sudden cardiac death (SCD), the leading cause of death in western countries. The treatment and costs associated with aging-related heart disease contribute to substantial personal, societal and economic burdens. Resolving the contributing mechanisms of heart disease is a pressing goal of basic and translational aging research. In all cells, including those of heart muscle, the ubiquitin-proteasome system (UPS) and autophagy/lysosome system provide proteolytic mechanisms to regulate protein turnover and degradation. The effective removal of protein aggregates and damaged mitochondria via autophagy might be crucial for the maintenance of homeostasis in heart and cardiac function. Although reduced autophagy is associated with many age-related heart diseases, it remains unknown whether altered autophagy with age is a contributing factor or merely a response to cardiac senescence. We have recently identified Activin signaling, a member of the TGF- superfamily, as a regulator for longevity and muscle autophagy in Drosophila. Very little is known whether and how Activin signaling might influence cardiomyopathy or its progression with age. In order to further understand the underlying mechanisms and translate our discovery in fly muscle to mammalian research, we will investigate the role of Activin in aging fly heart and simultaneously in homologous cardiomyocytes of a rabbit model of heart aging. Specifically, we will identify the molecular mechanisms through which Activin signaling controls autophagy using Drosophila cell culture (Aim 1). We will then determine how Activin signaling modulates myocardial cell autophagy and heart function of aging Drosophila (Aim 2). Finally we will translate our discovery in fly to mammalian cardiac system by dissecting the regulation of autophagy and tissue homeostasis by Activin signaling in aging rabbit cardiomyocytes (Aim 3). A better understanding of molecular mechanisms underlying the maintenance of heart tissue homeostasis will be critical for the development of therapeutic strategies for preventing cardiac dysfunction during aging. This Pathway to Independence award will help Dr. Hua Bai to achieve his career goal in many ways and help his transition to an independent investigator. Dr. Bai's long-term career goal is to establish an independent program at a major research university or biomedical research institute where he will lead and teach basic research on functional aging and age-related diseases, with an emphasis on autophagy and its roles in cardiac aging. During the K99 training phase, Dr. Bai will build his own translational expertise by simultaneously learning experimental systems of cardiac aging with Drosophila and the rabbit heart (an exceptional human model). While he will continue to be mentored by Dr. Marc Tatar, Dr. Bai will train with Dr. Gideon Koren, Director of Cardiovascular Research Center (CVRC) of Rhode Island Hospital, and Dr. Rolf Bodmer, Director of Development and Aging Program at Sanford Burnham Medical Research Institute. Both Dr. Koren and Dr. Bodmer are the experts in the field of cardiac aging and diseases. Dr. Bai will take advantage of this unique training opportunity to develop his capacity to translate research on cardiac function from Drosophila to mammals.